Dr. Joshua T Schiffer is completing Infectious Diseases fellowship and an MS degree in Epidemiology at the University of Washington in 2009. This proposal describes a 5-year training program, which will allow him to develop an independent academic career in clinical research and mathematical modeling of genital herpes simplex virus-2 (HSV-2) infection. Dr. Lawrence Corey is an internationally renowned leader in clinical HSV-2 research and is the mentor for this award. HSV-2 is the most prevalent cause of genital ulcers worldwide and has emerged as a significant risk factor for acquisition and transmission of HIV. HSV-2 transmission most frequently occurs during periods of asymptomatic genital shedding. Our group has recently used intensive sampling (swabbing the genital surfaces 4 times per day) to demonstrate that the majority of genital shedding episodes last less than 12 hours, suggesting a frequent reactivation rate from the ganglia and a brisk peripheral immune response. We recently designed a novel mathematical model of HSV replication and immune response that we fit to quantitative HSV PCR data derived from daily genital swabs performed during a genital lesion. The model was then run in a stochastic format over 365 days leading to novel hypotheses regarding pathogenesis. The goal of the current proposal is to prove several of these hypotheses by linking our model to more detailed prospectively gathered data including HSV copy number from frequent genital PCR swabs, CD8+ T-cell density from serial biopsies, and lesion size from photographs and serial measurements. We will also obtain individual parameter values for patients using experimental techniques. Aim 1 describes our protocol for gathering this data in 20 HIV positive and 20 HIV negative participants. In Aim 2, we propose performing biopsies before, and deriving model parameters during, successive shedding episodes in our participants. We seek to prove that CD8+ T-cell expansion will occur only during lesional shedding episodes but not during smaller low-copy shedding episodes, and that CD8+ T-cell density at episode onset inversely correlates with lesion size and peak HSV copy number. In Aim 3, we will swab patients intensively for 60 days to determine shedding frequency, and follow clinically for a year to determine recurrence frequency. We will then use prediction models to determine model parameters predict heterogeneity in these outcomes.